1,8-naphthyridine compounds

ABSTRACT

There is described 2-amino-5,7-disubstituted-naphthyridine and 5,7-disubstituted-naphthyridin-2(1H)-one derivatives with bronchodilating and hypotensive properties prepared by the reaction of 2,6-diaminopyridine with an appropriate β-diketone providing the 2-amino products. The 2-oxo analogs are prepared from the 2-amino products by treatment with nitrous acid.

This is a division of application Ser. No. 350,285 filed Apr. 11, 1973,now U.S. Pat. No. 3,843,663.

This invention is concerned with2-amino-5,7-disubstituted-1,8-naphthyridine and5,7-disubstituted-naphthyridin-2(1H)-one compounds and processes fortheir preparation.

The novel compounds of this invention have one of the general structuralformulae I or II ##SPC1##

wherein R⁵ is selected from lower alkyl having from 1 to 5 carbon atoms,halo substituted lower alkyl, preferably trifluoromethyl andpentafluoroethyl, phenyl, pyridyl, thienyl and naphthyl, R⁷ is selectedfrom lower alkyl having from 1 to 5 carbon atoms and halo-substitutedlower alkyl, preferably trifluoromethyl and pentafluoroethyl, and one orboth of the variable radicals R⁵ and/or R⁷ is a haloalkyl.

The 2-oxo products (II) are keto-enol tautomers. However as the ketoform is considered the more stable tautomer, the products herein will benamed as 2-oxo compounds although those skilled in the art will realizethat both tautomers may be present or any particular compound so namedmay exist as the enol or hydroxy tautomer and the following disclosuretherefore is to be interpreted to incorporate all tautomeric forms.

The naphthyridine compounds of this invention have been shown toincrease the concentration of 3',5'-cyclic adenosine monophosphate invitro and have been found in animal studies to inhibit bronchialconstriction induced by histamine and other constricting agents and aretherefore useful as bronchodilating agents. As bronchodilating agents,the products of this invention have been found to have relatively lowchronotropic effect as compared with known bronchial dilator agents.Additionally the products possess useful hypotensive properties.

The process aspect of our invention resides in the reaction of2,6-diaminopyridine with the appropriate β-diketone to provide the2-amino-5,7-disubstituted-1,8-naphthyridine compounds. The reaction isfacilitated by warming up to the boiling point although in practicelower temperatures, up to 90°-95° C., have been found to provideoperable conditions. When R⁵ and R⁷ represent dissimilar substituents,the reaction sometimes forms both isomers. When two isomers are obtainedthey can readily be separated by conventional methods, conveniently bychromatographic separation on silica gel using ethyl acetate,methanol-benzene, acetone, as well as other known developing solvents.

The 2-oxo compounds are obtained by treatment of the 2-amino compoundwith nitrous acid. The prior art procedure for converting2-amino-1,8-naphthyridine compounds to the corresponding 2-oxo compoundusing dilute sulfuric acid and sodium nitrite was found to beinoperative for the compounds of this invention having a haloalkylsubstituent attached to the naphthyridine nucleus. It was discovered,however, that for all of the products of this invention conversion ofthe 2-amino to the 2-oxo group could be effected by use oftrifluoroacetic acid or pentafluoropropionic acid and an alkali metalnitrite, suitably sodium or potassium nitrite which provides the 2-oxoanalog in good yield. Conversion takes place readily at ambienttemperature. Slight warming would not, however, be contraindicated.

The process for making the novel compounds of this invention can beillustrated schematically as follows: ##SPC2##

The following examples will provide details of the reaction conditionsemployed in preparing the compounds as well as illustrate thepreparation of certain compounds falling within the scope of thisinvention.

EXAMPLE 1 2-Amino-5,7-di(trifluoromethyl)-1,8-naphthyridine

A mixture of 2,6-diaminopyridine (5.2 g., 47.6 mmole),1,1,1,5,5,5-hexafluoroacetylacetone (10.0 g., 48.0 mmole) and 85%phosphoric acid (50 ml.) are stirred for 6 hours in an oil-bath at90°-95° C. then left overnight at ambient temperature. The reactionmixture is poured into ice water and neutralized with ammonium hydroxideto pH 7, the solid collected, washed with water and dried to provide 9.0g. (67%) of product, m.p. 198°-204° C. Upon recrystallization frombenzene, purified product separates in the form of pale yellow needles,m.p. 204°-206° C.

Analysis calculated for C₁₀ H₅ F₆ N₃ : C, 42.72, H, 1.79, F, 40.54, N,14.94 . Found: C, 42.77, H, 2.13, F, 40.33, N, 15.23.

EXAMPLE 2 2-Amino-5-methyl-7-trifluoromethyl-1,8-naphthyridine and2-Amino-5-trifluoromethyl-7-methyl-1,8-naphthyridine

By replacing the hexafluoroacetylacetone employed in Example 1 by anequivalent quantity of 1,1,1,-trifluoroacetylacetone and followingsubstantially the same procedure described in Example 1, there isobtained a mixture of the two products which are isolated from the crudereaction mixture by chromatographic separation on silica gel using ethylacetate as the developing agent. There is thus obtained a 17.6% yield of2-amino-5-methyl-7-trifluoromethyl-1,8-naphthyridine which melts at255°-257° C. following purification by recrystallization from toluene.

Analysis calculated for C₁₀ H₈ F₃ N₃ : C, 52.87, H, 3.55, F, 18.50, N,25.08; Found: C, 52.69, H, 3.75, F, 18.77, N, 25.41; and a 20.6% yieldof 2-amino-5-trifluoromethyl-7-methyl-1,8-naphthyridine which melts at195°-197° C. (dec.) following recrystallization from benzene.

Analysis Found: C, 52.99, H, 3.75, F, 18.79, F, 25.18.

EXAMPLE 3 2-Amino-5-(2-thienyl)-7-trifluoromethyl-1,8-naphthyridine

By replacing the hexafluoroacetylacetone employed in Example 1 by anequivalent quantity of 1-trifluoromethyl-5-(2-thienyl)-propan-1,3-dioneand following substantially the same procedure described in Example 1there is obtained a 15.3% yield of product which melts at 256°-258° C.after recrystallization from ethyl acetate.

Analysis calculated for C₁₃ H₁₀ F₃ N₃ S: C, 52.88, H, 2.73; N, 14.23, F,19.30. Found: C, 53.39, H, 2.84, N, 13.87, F, 19.26; C, 53.09, H, 2.95,N, 14.43, F, 19.24.

EXAMPLE 4 5,7-Di(trifluoromethyl)-1,8-naphthyridine-2(1H)-one

2-Amino-5,7-ditrifluoromethyl-1,8-naphthyridine, prepared as describedin Example 1, (5.60 g., 20 mmoles) is dissolved in trifluoroacetic acid(40 ml.). To the stirred, cooled (ice bath), solution is added finelypowdered sodium nitrite (3.0 g., 43.5 mmoles) in small portions.Stirring is continued at room temperature for 1 hour, the mixture thenpoured into a crushed ice/water mixture (ca. 500 ml.), and the productfiltered off and dried in an oven at 60° C. yielding 4.2 g. (75%) ofcrude product. Following purification by recrystallization fromisopropyl ether there is obtained 3.4 g. (60%) of pure product, m.p.182°-184° C.

Analysis calculated for C₁₀ H₄ F₆ N₂ O: C, 42.57, H, 1.43, F, 40.40, N,9.92; Found: C, 43.02, H, 1.66, F, 40.25, N, 10.22.

By following the procedure of Example 4 but replacing the2-amino-5,7-di(trifluoromethyl)-1,8-naphthyridine by an equivalentquantity of the products of Examples 2 and 3, respectively, that is byemploying

2-amino-5-methyl-7-trifluoromethyl-1,8-naphthyridine

2-amino-5-trifluoromethyl-7-methyl-1,8-naphthyridine

2-amino-5-(2-thienyl)-7-trifluoromethyl-1,8-naphthyridine,

there is obtained, respectively.

EXAMPLE 5

5-Methyl-7-trifluoromethyl-1,8-naphthyridin-2(1H)-one,

69% yield, m.p. 200°-202° C.

Analysis calculated for C₁₀ H₇ F₃ N₂ O: C, 52.64, H, 3.09, F, 24.97, N,12.27; Found: C, 52.39, H, 3.52, F, 25.10, N, 12.36.

EXAMPLE 6

5-Trifluoromethyl-7-methyl-1,8-naphthyridin-2(1H)-one, 35% yield, m.p.165°-167° C. following recrystallization from ethyl acetate.

Analysis calculated for C₁₀ H₇ F₃ N₂ O: C, 52.64, H, 3.09, F, 24.97, N,12.27; Found: C, 52.70, H, 3.21, F, 25.32, N, 12.47.

EXAMPLE 7

5-(2-Thienyl)-7-trifluoromethyl-1,8-naphthyridin-2(1H)-one, 12% yield,m.p. 103° C. following recrystallization from ethyl acetate.

Analysis calculated for C₁₃ H₇ F₃ N₂ OS: C, 52.70, H, 2.38, F, 19.23, N,9.45, S, 10.82; Found: C, 53.17, H, 2.15, F, 19.41, N, 9.35, S, 11.08.

The products identified in Table I are prepared by the methods describedin Examples 1 and 4. The 2-amino products having the substituents 5- and7- are prepared by replacing the 1,1,1,5,5,5-hexafluoroacetylacetoneemployed in Example 1 by an equivalent quantity of the β-diketoneidentified in the table. When a mixture of isomers is obtained they areseparated by known chromatographic methods such as described herein andillustrated in Example 2. The 2-oxo analog of each product is obtainedby nitrozation of the amino group as described in Example 4.

TABLE I ##SPC3##

    Ex. No.    R.sup.5      R.sup.7                                               ______________________________________                                        8          t-butyl      trifluoromethyl                                       9          ethyl        trifluoromethyl                                       10         isobutyl     trifluoromethyl                                       11         isopropyl    trifluoromethyl                                       12         2-naphthyl   trifluoromethyl                                       13         isopentyl    trifluoromethyl                                       14         phenyl       trifluoromethyl                                       15         3-pyridyl    trifluoromethyl                                       ______________________________________                                    

EXAMPLE 16 2-Amino-5,7-di(pentafluoroethyl)-1,8-naphthyridine

Step A: Preparation of 1,1,1,2,2,6,6,7,7,7,-Decafluoroheptan-3,5-dione

To a stirred suspension of potassium t-butoxide (44.8 g., 0.4 mole) indry ether (400 ml.) is added ethyl pentafluoropropionate (76.8 g., 0.4mole) over a period of about 15 minutes. Most of the solid dissolves. Asolution of pentafluoroethyl methyl ketone (64.8 g., 0.4 mole) in dryether (60 ml.) is added slowly, and after stirring the mixture for 2hours at room temperature, it is allowed to stand overnight. A solutionof glacial acetic acid (27.2 ml.) in water (120 ml.) is added withstirring and external cooling (ice-bath). Then a warm solution of copperacetate (56.0 g., 0.23 mole) in water (532 ml.) is added slowly withstirring and cooling. The ether is distilled off, and the copper salt ofthe product is collected by filtration, washed with water, drainedthoroughly, and then washed with petroleum ether. The copper derivativeis suspended in ether (200 ml.) and decomposed by treatment with 15%sulphuric acid (450 ml.). The aqueous layer is separated and extractedwith more ether (3 × 50 ml.). The combined ethereal extract is dried,first over anhydrous sodium sulphate and then over anhydrous calciumsulphate. Evaporation of the ether gives the product which is purifiedby fractionational distillation at atmospheric pressure.

Step B: Preparation of2-Amino-5,7-di(pentafluoroethyl)-1,8-naphthyridine

A mixture of 2,6-diamino pyridine (5.2 g., 4.76 mmole),1,1,1,2,2,6,6,7,7,7-decafluoroheptan-3,5-dione (14.5 g., 4.80 mmole) and85% phosphoric acid (50 ml.) is stirred at 90°-95° C. for 6 hours. Whencool, the reaction mixture is poured into ice-water and neutralized withammonium hydroxide to pH 7. The solid is collected, washed with water,dried, and can be purified by recrystallization from benzene.

EXAMPLE 17 2-Amino-5-methyl-7-pentafluoroethyl-1,8-naphthyridine and2-Amino-7-methyl-5-pentafluoroethyl-1,8-naphthyridine

When the decafluoroheptanedione in the foregoing example is replaced by1,1,1,2,2-pentafluorohexane-3,5-dione (9.80 g., 4.80 mmole), the crudeproduct is a mixture of two isomeric naphthyridines. The two compounds,2-amino-5-methyl-7-pentafluoroethyl-1,8-naphthyridine and2-amino-7-methyl-5-pentafluoroethyl-1,8-naphthyridine, are separated bychromatography on silica gel using ethyl acetate or carbontetrachloride/chloroform as the solvent phase, and purified byrecrystallizing the separated fractions from benzene.

EXAMPLE 18 5-Methyl-7-pentafluoroethyl-1,8-naphthyridin-2(1H)-one

2-Amino-5-methyl-7-pentafluoroethyl-1,8-naphthyridine (5.54 g., 20mmole) is dissolved in trifluoroacetic acid (40 ml.) and to the stirredsolution cooled to -5° to 0° C. is added finely powdered sodium nitrite(3.0 g., 43.5 mmole) in small portions. Stirring of the mixture iscontinued at room temperature for one hour, after which it is pouredinto ice-water (ca. 500 ml.). The product precipitates and is collected,washed and dried at 60° C. in air. It can be purified byrecrystallization from diisopropyl ether.

EXAMPLE 19 7-Methyl-5-pentafluoroethyl-1,8-naphthyridin-2(1H)-one

7-Methyl-5-pentafluoroethyl-1,8-naphthyridin-2(1H)-one is obtained in asimilar way, when 2-amino-7-methyl-5-pentafluoroethyl-1,8-naphthyridineis substituted for 2-amino-5-methyl-7-pentafluoroethyl-1,8-naphthyridinein the foregoing example.

EXAMPLE 20 5,7-Di(pentafluoroethyl)-1,8-naphthyridin-2(1H)-one

When an equivalent amount (7.62 g., 20 mmole) of2-amino-5,7-di(pentafluoroethyl)-1,8-naphthyridine is used in place ofthe 2-amino-5-methyl-7-pentafluoroethyl-1,8-naphthyridine employed inExample 18, the product is5,7-di(pentafluoroethyl)-1,8-naphthyridin-2(1H)-one. Purification iseffected by recrystallization of the crude product from a mixture ofbenzene and petroleum ether.

The products of this invention were found, when tested according tostandard protocols in anesthetized dogs to inhibit bronchialconstruction induced by one or more bronchoconstricting agents; a knownprocedure for evaluating the bronchodilating properties of products. Inaddition, the compounds were also found to exhibit hypotensiveproperties, probably due to their action as peripheral vasodilators andare therefore potentially useful for the treatment of hypertension.Intravenous or intraduodenal doses in the approximate dose range of 5mg./kg. to 75 mg./kg. provided protection at the ED₅₀ level against theinduced bronchoconstriction in most animals challenged. Those compoundsthat also exhibited hypotensive properties were effective within thesame dosage range.

The invention further provides pharmaceutical compositions comprising,as active ingredient, at least one of the compounds according to theinvention in association with a pharmaceutical carrier or excipient towhich other active ingredients can be added, if desired. The product orproducts may be presented in a form suitable for application orally(such as capsules, tablets or liquid preparations), or for parenteraladministration (in the form of solutions or suspensions) or in aerosolsprepared by conventional methods. For example, a capsule can be preparedby conventional methods employing lactose as an excipient and containingper unit dosage 10-25 mgs. of active compound. Unit dosages can rangebetween about 5 to 100 mg. of administration as prescribed by thephysician.

While the invention has been illustrated by certain specific members ofthe novel 1,8-naphthyridine products made by certain specific methodsand formulated into certain specific dosage forms, it is to beunderstood that the invention is not to be considered limited by or tothe specific embodiments illustrated but is to encompass other membersof the novel products falling within the scope of the generic disclosureand claims as well as other methods or modifications of the methodsdescribed for their preparation and other formulations, all of whichwould be obvious in view of the teaching herein to one skilled in theart.

We claim:
 1. A 1,8-naphthyridine having one of the structures A or B ##SPC4##wherein R⁵ is selected from the group consisting of lower alkyl, trifluoromethyl, pentafluoroethyl, phenyl, pyridyl, thienyl, and naphthyl; R⁷ is selected from the group consisting of lower alkyl, trifluoromethyl and pentafluoroethyl, and at least one of the variable radicals R⁵ or R⁷ is trifluoromethyl or pentafluoroethyl.
 2. A compound as claimed in claim 1 wherein R⁵ is 2-thienyl and R⁷ is trifluoromethyl.
 3. A compound as claimed in claim 1 wherein R⁵ is lower alkyl and R⁷ is trifluoromethyl or pentafluoroethyl.
 4. A compound as claimed in claim 1 having the structural formula A wherein R⁵ and R⁷ have the meaning assigned in claim
 1. 5. A compound as claimed in claim 1 wherein R⁵ and R⁷ are each trifluoromethyl.
 6. A compound as claimed in claim 1 having the structural formula B wherein R⁵ and R⁷ have the meaning assigned in claim
 1. 7. A compound as claimed in claim 1 wherein R⁵ is methyl and R⁷ is trifluoromethyl.
 8. A compound as claimed in claim 1 wherein R⁵ is trifluoromethyl and R⁷ is methyl. 